1352072-85-5Relevant academic research and scientific papers
Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction
Rew, Yosup,Sun, Daqing,Yan, Xuelei,Beck, Hilary P.,Canon, Jude,Chen, Ada,Duquette, Jason,Eksterowicz, John,Fox, Brian M.,Fu, Jiasheng,Gonzalez, Ana Z.,Houze, Jonathan,Huang, Xin,Jiang, Min,Jin, Lixia,Li, Yihong,Li, Zhihong,Ling, Yun,Lo, Mei-Chu,Long, Alexander M.,McGee, Lawrence R.,McIntosh, Joel,Oliner, Jonathan D.,Osgood, Tao,Saiki, Anne Y.,Shaffer, Paul,Wang, Yu Chung,Wortman, Sarah,Yakowec, Peter,Ye, Qiuping,Yu, Dongyin,Zhao, Xiaoning,Zhou, Jing,Medina, Julio C.,Olson, Steven H.
, p. 10499 - 10511 (2014)
Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.
